tbuckley/cabot-search huggingface dataset:
Phase Ib study of pembrolizumab in combination with trastuzumab emtansine for metastatic HER2-positive breast cancer
Authors: Adrienne G Waks, Tanya E Keenan, Tianyu Li, Nabihah Tayob, Gerburg M Wulf, Edward T Richardson, Victoria Attaya, Leilani Anderson, Elizabeth A Mittendorf, Beth Overmoyer, Eric P Winer, Ian E Krop, Judith Agudo, Eliezer M Van Allen, Sara M Tolaney
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Preclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine (T-DM1) combined with pembrolizumab is unknown. Methods This was a single-arm phase Ib trial (registration date January 26, 2017) of T-DM1 plus pembrolizumab in metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible patients had HER2-positive, metastatic breast cancer previously treated with taxane, trastuzumab, and pertuzumab, and were T-DM1-naïve. A dose de-escalation design was used, with a dose-finding cohort followed by an expansion cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies. The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Immune biomarkers were assessed using histology, protein/RNA expression, and whole exome sequencing. Associations between immune biomarkers and treatment response, and biomarker changes before and during treatment, were explored. Results 20 patients received protocol therapy. There were no dose-limiting toxicities. The RP2D was 3.6 mg/kg T-DM1 every 21 days plus 200 mg pembrolizumab every 21 days. 85% of patients experienced treatment-related adverse events (AEs) ≥grade 2, 20% of patients experienced grade 3 AEs, and no patients experienced grade &gt;4 AEs. Four patients (20%) experienced pneumonitis (three grade 2 events; one grade 3 event). ORR was 20% (95% CI 5.7% to 43.7%), and median PFS was 9.6 months (95% CI 2.8 to 16.0 months). Programmed cell death ligand-1 and tumor infiltrating lymphocytes did not correlate with response in this small cohort. Conclusions T-DM1 plus pembrolizumab was a safe and tolerable regimen. Ongoing trials will define if there is a role for checkpoint inhibition in the management of HER2-positive metastatic breast cancer. Trial registration number NCT03032107 .
IgE type multiple myeloma exhibits hypermutated phenotype and tumor reactive T cells
Authors: Niklas Kehl, Michael Kilian, Julius Michel, Tim R Wagner, Sebastian Uhrig, Alexander Brobeil, Lilli-Sophie Sester, Sven Blobner, Simon Steiger, Michael Hundemer, Niels Weinhold, Karsten Rippe, Stefan Fröhling, Stefan B Eichmüller, Lukas Bunse, Carsten Müller-Tidow, Hartmut Goldschmidt, Michael Platten, Marc-Steffen Raab, Mirco J Friedrich
Journal: Journal for ImmunoTherapy of Cancer (2022)

Multiple myeloma (MM) is a hematological malignancy originating from malignant and clonally expanding plasma cells. MM can be molecularly stratified, and its clonal evolution deciphered based on the Ig heavy and light chains of the respective malignant plasma cell clone. Of all MM subtypes, IgE type MM accounts for only &lt;0.1% of cases and is associated with an aggressive clinical course and consequentially dismal prognosis. In such malignancies, adoptive transfer of autologous lymphocytes specifically targeting presented (neo)epitopes encoded by either somatically mutated or specifically overexpressed genes has resulted in substantial objective clinical regressions even in relapsed/refractory disease. However, there are no data on the genetic and immunological characteristics of this rare and aggressive entity. Here, we comprehensively profiled IgE type kappa MM on a genomic and immune repertoire level by integrating DNA- and single-cell RNA sequencing and comparative profiling against non-IgE type MM samples. We demonstrate distinct pathophysiological mechanisms as well as novel opportunities for targeting IgE type MM. Our data further provides the rationale for patient-individualized neoepitope-targeting cell therapy in high tumor mutation burden MM.
Efficacy of cetuximab plus PD-1 inhibitor differs by HPV status in head and neck squamous cell carcinoma: a systematic review and meta-analysis
Authors: Siqi Zhang, Mengge Zheng, Deheng Nie, Lili Xu, Huimin Tian, Mengmeng Wang, Wenjia Liu, Zhenbang Feng, Fujun Han
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The addition of cetuximab significantly increased the antitumor effect of programmed cell death protein 1 (PD-1) inhibitors in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, preliminary analyses suggested that human papillomavirus (HPV)-positive disease benefited less than HPV-negative disease. Therefore, we conducted a meta-analysis to assess whether the efficacy of the combination therapy varied according to HPV status in HNSCC. Methods We identified clinical trials of patients with recurrent or metastatic HNSCC who received PD-1 inhibitor monotherapy or the combination therapy of cetuximab plus a PD-1 inhibitor. The participants were divided into four groups based on the type of therapy (combination vs monotherapy) and HPV status (positive vs negative). We focused on three comparisons (monotherapy vs combination therapy by HPV status and HPV-positive vs HPV-negative disease in combination therapy). The primary and secondary endpoints were objective response rate (ORR) and 1-year overall survival (OS) rate, respectively. The ORR and 1-year OS rate were pooled using random-effects models for each group and were compared for the different comparisons. Results Overall, 802 patients from seven trials were eligible for the ORR assessment; of which, 684 patients received PD-1 inhibitor monotherapy and 118 patients underwent the combination therapy. Compared with PD-1 inhibitor monotherapy, the addition of cetuximab improved the ORR in HPV-negative disease (pooled ORR in monotherapy vs combination therapy: 15% vs 46%, p&lt;0.001) but not in HPV-positive disease (17% vs 18%, p=0.686). The efficacy of adding cetuximab was consistent for the 1-year OS rate in HPV-negative disease (pooled 1-year OS rate in monotherapy vs combination therapy: 36% vs 59%, p&lt;0.001) and in HPV-positive disease (40% vs 55%, p=0.252). After the combination therapy, HPV-positive disease had a significantly lower ORR than HPV-negative disease (odds ratio: 0.29, p=0.004), but no differences were shown in the 1-year OS rate. Conclusions Our meta-analysis suggests that the addition of cetuximab to a PD-1 inhibitor is more effective compared with PD-1 inhibitor monotherapy only in patients with HPV-negative HNSCC. Despite the retrospective nature of this meta-analysis, these findings should help in designing relevant clinical trials rationally.
Silencing mouse circular RNA circSlc8a1 by circular antisense cA-circSlc8a1 induces cardiac hepatopathy
Authors: Nan Wu, Feiya Li, Weining Yang, William W. Du, Faryal Mehwish Awan, Chao Zhang, Juanjuan Lyu, Sema Misir, Kaixuan Zeng, Esra Eshaghi, Burton B. Yang
Journal: Molecular Therapy (2022)

Circular RNAs (circRNAs) are a group of non-coding RNAs with a unique circular structure generated by back-splicing. It is acknowledged that circRNAs play critical roles in cardiovascular diseases. However, functional studies of circRNAs were impeded due to lack of effective in vivo silencing approaches. Since most circRNAs are produced by protein-coding transcripts, gene editing typically affects the coding activity of the parental genes. In this study, we developed a circular antisense RNA (cA-circSlc8a1) that could silence the highly expressed circRNA circSlc8a1 in the mouse heart but not its parental Slc8a1 linear mRNA. Transgenic cA-circSlc8a1 mice developed congestive heart failure resulting in a significant increase in the body weight secondary to peripheral edema and congestive hepatopathy. To further test the role of circSlc8a1, we generated transgenic mice overexpressing circSlc8a1 and observed a protective effect of circSlc8a1 in a pressure overload model. Mechanistically, we found that circSlc8a1 translocated into mitochondria to drive ATP synthesis. While establishing a transgenic murine model for antisense-mediated circRNA silencing without interfering with the parental linear RNA, our finding revealed the essential role of circSlc8a1 in maintaining heart function and may lay the groundwork of using the circular antisense RNA as a potential gene therapy approach for cardiovascular diseases. Circular RNAs (circRNAs) are a group of non-coding RNAs with a unique circular structure generated by back-splicing. It is acknowledged that circRNAs play critical roles in cardiovascular diseases. However, functional studies of circRNAs were impeded due to lack of effective in vivo silencing approaches. Since most circRNAs are produced by protein-coding transcripts, gene editing typically affects the coding activity of the parental genes. In this study, we developed a circular antisense RNA (cA-circSlc8a1) that could silence the highly expressed circRNA circSlc8a1 in the mouse heart but not its parental Slc8a1 linear mRNA. Transgenic cA-circSlc8a1 mice developed congestive heart failure resulting in a significant increase in the body weight secondary to peripheral edema and congestive hepatopathy. To further test the role of circSlc8a1, we generated transgenic mice overexpressing circSlc8a1 and observed a protective effect of circSlc8a1 in a pressure overload model. Mechanistically, we found that circSlc8a1 translocated into mitochondria to drive ATP synthesis. While establishing a transgenic murine model for antisense-mediated circRNA silencing without interfering with the parental linear RNA, our finding revealed the essential role of circSlc8a1 in maintaining heart function and may lay the groundwork of using the circular antisense RNA as a potential gene therapy approach for cardiovascular diseases.
PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way
Authors: Xiaolu Yu, Yiru Long, Binfan Chen, Yongliang Tong, Mengwen Shan, Xiaomin Jia, Chao Hu, Meng Liu, Ji Zhou, Feng Tang, Henglei Lu, Runqiu Chen, Pan Xu, Wei Huang, Jin Ren, Yakun Wan, Jianhua Sun, Jia Li, Guangyi Jin, Likun Gong
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Various tumors are insensitive to immune checkpoint blockade (ICB) therapy. Toll-like receptors (TLRs) establish the link between innate and adaptive immunity, which can assist T-cell activation and serve as promising targets for combination to enhance ICB therapy. Here, we aimed to improve efficacy for anti-programmed death ligand 1 (PD-L1) therapy by developing a PD-L1/TLR7 dual-targeting nanobody-drug conjugate (NDC), based on the PD-L1 nanobodies and TLR7 agonist we developed. Methods PD-L1 nanobodies were obtained by phage display screening and identified through T-cell activation bioassay, in vivo imaging and quantitative biodistribution study. Immune activation and PD-L1-inducing of TLR7 agonists were evaluated in diverse innate cell models. We constructed PD-L1/TLR7 dual-targeting NDCs by chemically coupling PD-L1 nanobodies and TLR7 agonists. The antitumor effect was evaluated via several murine or humanized solid tumor models. Immunophenotyping, immune cell depletion, tumor rechallenge, RNA sequencing and PD-L1-deficient models were combined to determine the mechanism for NDCs function. The dynamics of the in vivo behaviors of NDCs were assessed based on multiorgan changes in PD-L1 levels. Results The screened PD-L1 nanobodies were characterized as tumor-targeting and alleviated T-cell immunosuppression. The TLR7 agonists induced broad innate immune responses and intratumoral PD-L1 expression on antigen-presenting cells (APCs), and its antitumor effect was dependent on intratumoral delivery. The combination of TLR7 agonists and PD-L1 nanobodies activated both innate and adaptive immunity and upregulated PD-L1-related signaling pathways. After coupling to form dual-targeting NDCs, TLR7 agonists and PD-L1 nanobodies exerted synergistic antitumor effects and safety in either ‘hot’ or ‘cold’ tumor and early or advanced tumor models, reshaped the tumor immune microenvironment and induced antitumor immune memory. CD8 + T cells and natural killer cells were the main effector cells for NDCs to function. NDCs can promote PD-L1 expression on intratumoral APCs and tumor cells, and subsequently achieve targeted enrichment in tumors. Moreover, the efficacy of NDCs is biased toward dependence on host expression of PD-L1. Conclusions The novel PD-L1/TLR7 dual-targeting NDC exhibited potent efficacy against heterogeneous tumors through orchestrating innate and adaptive immunity, which could act as a promising strategy to improve ICB therapy and shows prospects for clinical development.
Immunosuppressive lncRNA LINC00624 promotes tumor progression and therapy resistance through ADAR1 stabilization
Authors: Qi Zhang, Bingqiu Xiu, Liyi Zhang, Ming Chen, Weiru Chi, Lun Li, Rong Guo, Jingyan Xue, Benlong Yang, Xiaoyan Huang, Zhi-Ming Shao, Shenglin Huang, Yayun Chi, Jiong Wu
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Despite the success of HER2-targeted therapy in achieving prolonged survival in approximately 50% of treated individuals, treatment resistance is still an important challenge for HER2+ breast cancer (BC) patients. The influence of both adaptive and innate immune responses on the therapeutic outcomes of HER2+BC patients has been extensively demonstrated. Methods Long non-coding RNAs expressed in non-pathological complete response (pCR) HER2 positive BC were screened and validated by RNA-seq. Survival analysis were made by Kaplan-Meier method. Cell death assay and proliferation assay were performed to confirm the phenotype of LINC00624. RT-qPCR and western blot were used to assay the IFN response. Xenograft mouse model were used for in vivo confirmation of anti-neu treatment resistance. RNA pull-down and immunoblot were used to confirm the interaction of ADAR1 and LINC00624. ADAR1 recombinant protein were purified from baculovirus expression system. B16-OVA cells were used to study antigen presentation both in vitro and in vivo. Flow cytometry was used to determine the tumor infiltrated immune cells of xenograft model. Antisense oligonucleotides (ASOs) were used for in vivo treatment. Results In this study, we found that LINC00624 blocked the antitumor effect of HER2- targeted therapy both in vitro and in vivo by inhibiting type I interferon (IFN) pathway activation. The double-stranded RNA-like structure of LINC00624 can bind and be edited by the adenosine (A) to inosine (I) RNA-editing enzyme adenosine deaminase RNA specific 1 (ADAR1), and this editing has been shown to release the growth inhibition and attenuate the innate immune response caused by the IFN response. Notably, LINC00624 promoted the stabilization of ADAR1 by inhibiting its ubiquitination-induced degradation triggered by β-TrCP. In contrast, LINC00624 inhibited major histocompatibility complex (MHC) class I antigen presentation and limited CD8+T cell infiltration in the cancer microenvironment, resulting in immune checkpoint blockade inhibition and anti-HER2 treatment resistance mediated through ADAR1. Conclusions In summary, these results suggest that LINC00624 is a cancer immunosuppressive lncRNA and targeting LINC00624 through ASOs in tumors expressing high levels of LINC00624 has great therapeutic potential in future clinical applications.
Localized ablative immunotherapy drives de novo CD8<sup>+</sup>T-cell responses to poorly immunogenic tumors
Authors: Ashley R Hoover, Saghar Kaabinejadian, Jason R Krawic, Xiao-Hong Sun, Abdul Rafeh Naqash, Qian Yin, Xinbo Yang, K Christopher Garcia, Mark M Davis, William H Hildebrand, Wei R Chen
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Localized ablative immunotherapies hold great promise in stimulating antitumor immunity to treat metastatic and poorly immunogenic tumors. Tumor ablation is well known to release tumor antigens and danger-associated molecular patterns to stimulate T-cell immunity, but its immune stimulating effect is limited, particularly against metastatic tumors. Methods In this study, we combined photothermal therapy with a potent immune stimulant, N-dihydrogalactochitosan, to create a local ablative immunotherapy which we refer to as laser immunotherapy (LIT). Mice bearing B16-F10 tumors were treated with LIT when the tumors reached 0.5 cm 3 and were monitored for survival, T-cell activation, and the ability to resist tumor rechallenge. Results We found that LIT stimulated a stronger and more consistent antitumor T-cell response to the immunologically ‘cold’ B16-F10 melanoma tumors and conferred a long-term antitumor memory on tumor rechallenge. Furthermore, we discovered that LIT generated de novo CD8 + T-cell responses that strongly correlated with animal survival and tumor rejection. Conclusion In summary, our findings demonstrate that LIT enhances the activation of T cells and drives de novo antitumor T-cell responses. The data presented herein suggests that localized ablative immunotherapies have great potential to synergize with immune checkpoint therapies to enhance its efficacy, resulting in improved antitumor immunity.
Climate emergency: Medical royal colleges unite to highlight effects on health
Authors: Tom Moberly
Journal: BMJ (2022)

Leaders of medical royal colleges and organisations representing general medicine, surgery, psychiatry, paediatrics, general practice, and pharmacy cycled across London on 13 October to highlight the effects of air pollution and climate change on health.The 15 km route was coordinated by the UK Health Alliance on Climate Change as part of Ride for their Lives (https://climateacceptancestudios.com/ridefortheirlives), a worldwide campaign to inspire action on air pollution and the wider climate crisis.
Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial
Authors: Jesper D. Gunst, Marie H. Pahus, Miriam Rosás-Umbert, I-Na Lu, Thomas Benfield, Henrik Nielsen, Isik S. Johansen, Rajesh Mohey, Lars Østergaard, Vibeke Klastrup, Maryam Khan, Mariane H. Schleimann, Rikke Olesen, Henrik Støvring, Paul W. Denton, Natalie N. Kinloch, Dennis C. Copertino, Adam R. Ward, Winiffer D. Conce Alberto, Silke D. Nielsen, Maria C. Puertas, Victor Ramos, Jacqueline D. Reeves, Christos J. Petropoulos, Javier Martinez-Picado, Zabrina L. Brumme, R. Brad Jones, Julie Fox, Martin Tolstrup, Michel C. Nussenzweig, Marina Caskey, Sarah Fidler, Ole S. Søgaard
Journal: Nature Medicine (2022)
COX7A2L genetic variants determine cardiorespiratory fitness in mice and human
Authors: Giorgia Benegiamo, Maroun Bou Sleiman, Martin Wohlwend, Sandra Rodríguez-López, Ludger J. E. Goeminne, Pirkka-Pekka Laurila, Marie Klevjer, Minna K. Salonen, Jari Lahti, Pooja Jha, Sara Cogliati, José Antonio Enriquez, Ben M. Brumpton, Anja Bye, Johan G. Eriksson, Johan Auwerx
Journal: Nature Metabolism (2022)

Abstract Mitochondrial respiratory complexes form superassembled structures called supercomplexes. COX7A2L is a supercomplex-specific assembly factor in mammals, although its implication for supercomplex formation and cellular metabolism remains controversial. Here we identify a role for COX7A2L for mitochondrial supercomplex formation in humans. By using human cis -expression quantitative trait loci data, we highlight genetic variants in the COX7A2L gene that affect its skeletal muscle expression specifically. The most significant cis -expression quantitative trait locus is a 10-bp insertion in the COX7A2L 3′ untranslated region that increases messenger RNA stability and expression. Human myotubes harboring this insertion have more supercomplexes and increased respiration. Notably, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in humans. Accordingly, specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher maximal oxygen consumption, increased lean mass and increased energy expenditure. Furthermore, Cox7a2l expression in mice is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in humans and show that COX7A2L plays an important role in cardiorespiratory fitness, which could have broad therapeutic implications in reducing cardiovascular mortality.
Life expectancy losses and bounce-backs during the COVID-19 pandemic
Journal: Nature Human Behaviour (2022)

Life expectancy losses and bounce-backs during the COVID-19 pandemicLife expectancies diverged in 2021, approaching pre-pandemic levels in Western Europe and further worsening in Eastern Europe, USA and Chile.Life expectancy deficits in 2021 are almost solely explained by premature deaths due to COVID-19.Correspondingly, countries with a higher share of vaccinated individuals suffered the least life expectancy deficit. The questionThe COVID-19 pandemic disrupted long-standing trends of improvements in global mortality 1 .Analysis of mortality data confirmed that excess deaths in 2020 were predominantly the direct result of COVID-19 (ref. 2 ).Fortunately, by early 2021, vaccination campaigns had begun, and one could remain optimistic that 2020 was just a short-term shock to population health.Indeed, tracing back the development of life expectancy over the past century shows that, despite drastic temporary disruptions due to wars or pandemics, the overall trend continued to rise 3 .Thus, we asked whether 2021 indeed saw a recovery of improvements in global mortality, or whether we were headed for a longer period of stagnation in life expectancy.
Impact of adherence to hydroxyurea on health outcomes among patients with sickle cell disease
Authors: Hyeun Ah Kang, Jamie C. Barner, Kenneth A. Lawson, Karen Rascati, Robert C. Mignacca
Journal: American Journal of Hematology (2022)

Abstract Although new pharmaceutical therapy options have recently become available, hydroxyurea is still the most commonly used and affordable treatment option for sickle cell disease (SCD). This study aimed to update the evidence on hydroxyurea adherence and its association with clinical and economic outcomes among individuals with SCD. This retrospective study used Texas Medicaid claims data from 09/2011–08/2016. Individuals were included if they had ≥1 inpatient or ≥2 outpatient SCD diagnoses, had ≥1 hydroxyurea prescription, were 2–63 years of age, and were continuously enrolled in Texas Medicaid between 6 months before and 1 year after the first hydroxyurea prescription fill date (index date). Hydroxyurea adherence (Medication Possession Ratio; MPR), vaso‐occlusive crisis (VOC)‐related outcomes, healthcare utilization and expenditures (SCD‐related and all‐cause) during the 1 year following the index date were measured. Bivariate and multivariable analyses were used to address the study objectives. Among 1035 included individuals (age: 18.8 ± 12.5 years, female: 52.1%), 20.9% were adherent to hydroxyurea (defined as MPR≥0.8). After adjustment for demographic and clinical characteristics, compared to being non‐adherent, adhering to hydroxyurea was significantly associated with: a lower risk (Odds Ratio [OR] = 0.480, p = .0007) and hazard rate (Hazard Ratio [HR] = 0.748, p = .0005) of a VOC event, fewer VOC events (Incidence Rate Ratio [IRR] = 0.767, p = .0009), fewer VOC‐related hospital days (IRR = 0.593, p = .0003), fewer all‐cause and SCD‐related hospitalizations (IRR = 0.712, p = .0008; IRR = 0.707, p = .0008, respectively) and emergency department visits (IRR = 0.768, p = .0037; IRR = 0.746, p = .0041, respectively), and lower SCD‐related total healthcare expenditures (IRR = 0.796, p = .0266). Efforts to increase adherence to hydroxyurea could improve clinical and economic outcomes among individuals with SCD.